A determination of pan-pathogen antimicrobials?

Abstract

While antimicrobial drug development has historically mitigated infectious diseases that are known, COVID-19 revealed a dearth of 'in-advance' therapeutics suitable for infections by pathogens that have not yet emerged. Such drugs must exhibit a property that is antithetical to the classical paradigm of antimicrobial development: the ability to treat infections by any pathogen. Characterisation of such 'pan-pathogen' antimicrobials requires consolidation of drug repositioning studies, a new and growing field of drug discovery. In this review, a previously-established system for evaluating repositioning studies is used to highlight 4 therapeutics which exhibit pan-pathogen properties, namely azithromycin, ivermectin, niclosamide, and nitazoxanide. Recognition of the pan-pathogen nature of these antimicrobials is the cornerstone of a novel paradigm of antimicrobial development that is not only anticipatory of pandemics and bioterrorist attacks, but cognisant of conserved anti-infective mechanisms within the host-pathogen interactome which are only now beginning to emerge. Ultimately, the discovery of pan-pathogen antimicrobials is concomitantly the discovery of a new class of antivirals, and begets significant implications for pandemic preparedness research in a world after COVID-19.

Keywords: Bioterrorism; COVID-19; Drug repositioning; Host-pathogen interaction; Pan-pathogen antimicrobial; Pandemic.

Fig. 1

Casadevall and Pirofski’s damage-response framework of microbial pathogenesis. The y-axis denotes host damage as a function of the host response. Damage can occur throughout the host response, which is represented by a continuum from ‘weak’ to ‘strong’. Therapeutic intervention can shift the curve towards benefiting the host, as denoted by the arrow.

Fig. 2

Pharmacological profile of azithromycin, ivermectin, niclosamide, and nitazoxanideduring COVID-19 pneumonia pathogenesis. Establishment of pan-pathogen antimicrobials facilitates discovery of conserved pharmacological properties against multiple pathogen types. For example, lysosomotropicity has emerged as a desideratum for both antimalarial and antiviral therapeutics. Drug-disease interactions of each pan-pathogen antimicrobial can further provide mechanistic insights into the general nature of infection. In so doing, pan-pathogen antimicrobials can drive the unification of microbiological and immunological disciplines, first envisioned by Casadevall and Pirofski. Immunomodulation by cytokine suppression is a prospective hallmark of pan-pathogen antimicrobial pharmacology.